Medical Hypotheses I

I Ma&d ltJplhw (1991) 36,33-42 oLaa$malonmpuKLtd19!n

Does Prolactin Play a Role in Skin Biology and Pathology? R. PAUS Department of Dermatology, Yale University School of Medicine, New Haven, CT 06510, USA

Abstract - Despite its extensive repertoire of biological activities, which include the growth and osmoregulation of epithelial tissues as well as immunoregulatory properties, the potential significance of the pituitary hormone prolactin (PRL) for human skin biology and pathokqy has yet to be fully appreciated. In this essay, the hypothesis is presented that PRL acts as a neuroendocrine modulator of skin epithelial cell proliferation and of the skin immune system by forming a ‘prolactin-circuit’ between the central nervous system and the skin. Binding to specific skin receptors, modulation of cytokine release in the skin, and stimulation of somatomedin release by mesenchymal cells are among the suggested pathways by which PRL could affect epithelial cell growth in the skin. Potential feedback signals, arising from the skin and modifying pituitary PRL release, are briefly outlined. Centering on the role of PRL in both psoriasis and hair growth as models for studying the proposed PRL-skin connection, clinical and experimental evidence in support of this theory is discussed in the context of a ‘neuroimmunedermatological’ perspective.

Introduction

that PRL has not yet found more attention in dermatological research (though some illdefined role for Why should the human skin have anything to do with PRL in hair growth is appreciated (2, 3)). Because prolactin? Often referred to as the ‘hormone of ma- the mammary gland is a derivative of the epidermis ternity’ due to its prominent role during pregnancy and is considered to be phylogenetically related to and lactation (l), it certainly appears odd to discuss sweat glands, Hadley has suggested that the specialthis pituitary hormone in a dermatological context. ized mammotropic action of PRL in humans may On closer inspection, however, it turns out that pro- haveevolved from its more generalized action on inlactin (PRL) is an amazingly versatile bioregulator, tegumental structuresin other vertebrates(e.g. on hair unrivaled by any other known polypeptide hormone and sebaceous glands of mammals, feathers of birds, in its repertoire of biological actions, with potent epidermis of amphibians) (1). growth-regulatory effects on integumental structures This raises the question, whether PRL still plays in many species (1). Considering, furthermore, that a role in human skin. In view of the reawakening the mammary gland - allegedly the main target or- interest in endocrine-skin interactions and the fact that gan for PFU in mammalian species - is actually the skin is both a hormone-generating and a hormonean integumental derivative, it is indeed rather odd modifying tissue, in addition to being a hormone 33

34 target (4, 5). it is timely to systematically explore this possibility.This speculative essay therefore introduces the hypothesis that PRL acts as a neuroendocrine modulator of skin epithelial cell growth and of the skin immune system by forming a ‘prolactin-circuit’ between the skin and the CNS (see Fig. details: pp. 38-39).

Fig. Hypothesis: a ‘prolactin circuit’ links skin and CNS. (For discussion see text, pp. 38-39; abbreviations used: L (lymphocyte), NK (natural killer cell), MAC (macrcphage). Fib (dermal hoblast), EGF (epidermal growth factor), IL-l (mterleukin-1). HIST (histamine), VIT D3 (vitamin D3). VIP (vasoactive intestinal r_ol)y), bFGF (basic fibtoblast growth factor), STH (growth

Clearly, there is no single piece of evidence that alone would carry this hypothesis. Rather, it is a patchwork of clinical observations and experimental data pointing to a PRL-skin connection (so far, this widely ignored association has not been tested experimentally). Without pretending to provide definite answers and fully aware of the speculative nature of the concept presented here, this essay aims at speculating a new dermatological research focus on PRL that eventually should provide fresh insight into the neuroendocrine control of the skin under physiological and pathological conditions. PRL affects the growth, differentiation and function of a wide range of skin-related epithelial tissues in vertebrates of both sexes (for review, see 1). While this has long been appreciated, e.g. for amphibian skin and the human mammary gland, it was recently described that PRL stimulates the peptide hormone production of thymic epithelial cells (99), which share several interesting features and possibly functions with epidermal keratinocytes (both arc keratinizing epithelial cells, have common antigens, and produce factors implicated in T cell differentia-

MEDICAL I-lYKYlXE.5~

tion (28,30,104)). Less well-known is also that PRL may be involved in regulating ion and fluid transport in several other mammalian epithelial tissues such as the human kidney (cf. 105), the rat kidney and intestine as well as the human eccrine sweat gland, a skin appendage (for ref. see 100). Since PRL is the hormone responsible for lactation in mammals, has gonadotropic effects on the ovary in non-pregnant females and on the testis in males, and may exert reproduction-relatedneurochemicaleffects (modification of the stress response and of behavior during lactation? (6)), an important role for PRL in mammalian reproductive physiology is now appreciated (1). However, PRL may also contribute to the malignant degeneration of epithelial cells of the human reproductive system, since increasing evidence supports a tumor-promoting role for PRL in human breast (8) and prostate cancer (9, 10). Particularly fascinating are PRL’s morphogenic properties: in amphibians,PRL acts as a larval growth hormone, inhibits metamorphosis and is required for limb regeneration (7); in humans, the decidual cells of the pregnant uterus become active producers of PRL (decidualisation is a process of very rapid morphogenesis), and an increase in the local PRL level coincides with major developmental changes of the fetus (for review, see 1). The question seems justified whether these potent morphogenic properties of PRL might be exploited in mammalian skin during wound healing and tissue remodelling processes, such as the extensive morphological changes characterizing the different phases of the hair cycle (cf. 2, 33,41). In addition, PRL has immunomodulatory functions in rodent and human systems, which have been summarized as ‘immunopermissive’(19-26). Stimulation of antibody production by B lymphocytes (24). inhibition of T-suppressor lymphocyte function (23), support of macrophage-activating factor production by T cells (25), and modulation of T and B lymphocyte development (26) are among the immunodulatory properties discussed for PRL. Although the precise immunological role for PRL in humans has yet to be elucidated (cf. 16, 21, 22, 23). it is tempting to speculate that these ‘immunopermissive’actions of PRL can affect the immune status of the skin: the increasing insight into the existence of a defined ‘skin immune system’ (27, 28, 29) with a crucial role in the control of keratinwyte proliferation under physiological and pathological conditions (29-32) should designate PRL, an immunomodulatory hormone with special affinity to epithelial tissues, a prime object of systematic experimental study in immunodermatology,

ROLE OF PROLACl-lN IN SKIN BIOLOGY AND PATHOUIGY

The polypeptide hormone PRL is produced and secreted by acidophilic cells in the anterior pituitary gland (‘lactouophs’) under the regulatory influence of higher brain centers, endogenous and external stimuli (e.g. estrogens, sleep, stress, sexual intercourse, food intake, drugs and cutaneous sensations such as nipple stimulation). Inhibitory signals from the hypothalamus (mainly dopamine) are thought to provide the dominant control system from pituitary PRL release, which explains the drastic inhibitory effect of the dopaminergic drug bromocriptine on pituitary PRL secretion (see below). This secretion is pulsatile and exhibits a circadian rhythm, with peak serum levels occurring during sleep, and a transient, physiological hyperprolactinemiain pregnant women and during lactation (for review, see 1, 11, 87). Only recently it has become appreciated that there are also extrapituitary sites of PRL production in humans, which may include the choriondecidual tissue of the pregnant uterus (1, 12, 13), the corpus luteurn (14), peripheral blood lymphocytes (16, cf. 17, 18) and, most noteworthy in the context of this hypothesis, human eccrine sweat glands (100) as well as selected connective tissue sites (15). This has invited the speculation that the capacity for extrapituitary PRL production is a general property of mesenchymal cells that serves local autocrine and paracrine functions (cf. 15) and poses the question, whether PRL might even be produced locally in the skin. Since hair growth and psoriasis can serve as model systems for the study of epithelial-mesenchymal interactions under physiological and pathological conditions respectively, they are particularly attractive for probing the PRL hypothesis presented here (both hair growth and psoriasis are characterized by rapid, highly controlled, mesenchymedependent, and in some respects strikingly similar proliferation of epithelial cells (cf. 33). Thus, we shall first examine hair growth for indications pointing toward a role for PRL in normal skin biology. Then, psoriasis is discussed as a field to study exemplarily PRL’s putative role in skin pathology, before, finally, a hypothetical circuitry, linking skin and CNS via PRL, is projected. Prolactin and skin biology: hair growth

Although hair growth and the hair cycle are probably under the dominant control of a growth regulatory system intrinsic to the skin, extrinsic factors, such as steroid, thyroid and pituitary hormones, also can profoundly influence the growth of the hair follicle (2,106). Of those factors, PRL has been der.onstrated

35 to directly or indirectly modulate hair growth, Shed-

ding and the molting cycle in a variety of species (2, 34, 35). while distinct effects of pregnancy and lactation on the follicular cycle (2) and an increased 6equency of hypertrichosis during pregnancy (36) are recognized. The underlying molecular mechanisms, however, remain obscure, mainly because they have rarely been studied. In women, hyperprolactinemiais one of the causes of hirsutism (3, 37). This excessive growth of male-pattern hair may be successfully tmated with bromocriptine (37), a dopaminergic drug that very effectively lowers PRL serum levels (11). Hair loss, vice versa, is an appreciated side-effect of bromocriptine therapy in females (38). (Although bromocriptine does not alter PRL levels alone, this is by far its most prominent and most reproducible effect (cf. 11)). A role for PRL in the induction and/or maintenance of hair growth might also explain why estrogens prolong the growth phase (anagen)of the hair cycle (39), since they am among the most potent stimulators of pituitary PRL release (1, 11). Because PRL can modulate peripheral androgen metabolism (40). it could as well affect hair growth indirectly via the well-documented site-specific action of androgens on the hair follicle (293%. Recently, we have shown that the immunosuppressive drug cyclosporine A (CsA) induces normal resting (telogen) hair follicles to enter the anagen phase of the growth cycle in mice (41). The development of hypertrichosis during immunosuppressive CsA therapy in humans, one of the most common side-effects of CsA (42), could be based on a similar ‘switchon’ phenomenon of human hair follicle growth. To explain our observation in mice, we have suggested a role for inhibitory cytokines in the regulation of normal hair growth: suppression of the production of these cytokines by CsA would disinhibit the resting follicle and ‘switch on’ anagen (33, 41). Based on PRL’s marked immunomodulatory properties (17, 19-26), the observation that PRL and CsA compete for binding to a common receptor (17,43,44), and that bromocriptine enhances the immunosuppressive activity of CsA (45), it is conceivable that PRL, also, exerts its effects on hair growth by interfering with hair follicle cytokine production. That PRL can indeed stimulate the production of peptide hormones by keratinized epithelial cells in mice (in vivo) and humans (in vitro) has recently been documented (99). A role for PRL in anagen induction is further supported by the observation that PRL can induce omithine decarboxylase (ODC), the rate limiting enzyme of polyamine biosynthesis (43), since ODC shows a sig-

36 niticantly higher activity in anagen than in telogen follicles (46). In fact, the whole pilosebaceous apparatus may respond to PRL: although the sebaceous glands seem to be primarily under the hormonal control of androgens, sebum production is affected by PRL and other pituitary hormones (47, 48) and is increased during pregnancy and lactation in humans (47). If one considers that sebaceous glands are holocrine, which means that the formation of sebum requires prior epithelial cell proliferation, this implies an action of PRL on the cell proliferation of theseglandular skin appendages of epidetmal origin. Another clue comes from the characteristic seborrhea of patients with Parkinson’s disease. This increased production of sebum tends to improve under the treatment with L-Dopa and/or bromocriptine (cf. 36, 49), both of which are potent inhibitors of pituitary PRL release (11). Also, acne vulgaris - a disease characterized by sebaceous gland hyperactivity and dysfunction can be associated with idiopathic hyperprolactinemia in the absence of altered androgen concentrations (in one study, e.g. 45% of women with acne (n=38) had high PRL serum levels) and can significantly be improved by bromocriptine therapy (47, SO).Taken together, these findings suggest a role for PRL not only in hair growth, but indeed in the regulation of the whole pilosebaceous apparatus, which should, therefore, serve as an exemplary study object for future experimental work on PRL’s proposed role in skin biology. Prolactinand skin pathology: psoriasis

That PRL may also be involved in cutaneous dysfunction can preferentially be studied in psoriasis. This very common inflammatory skin disease of still obscure etiology is characterized by epidermal hyperplasia and dyskeratinization on the basis of cellular and biochemical abnormalities, which involve keratinocytes, Langerhans cells, dermal fibroblasts, endothelial cells and T lymphocytes (51, 52). We have previously suggested that PRL may contribute to the induction of the psoriatic epidermal lesion (33). ‘lhough it is not proposed here that PRL plays a primary role in the etiopathogenesis of psoriasis, circumstantial evidence suggests that PRL may be an important contributory factor to the development and clinical course of psoriasis, whose pharmacological manipulation could assist in the management of this disease. It has been claimed that bromocriptine is effective in inducing remissions of psoriatic epidermal lesions

MEIXCAL HyPolBEsEs (53.54). Even though the therapeutic concept as well as the actual results of bromocriptine treatment are quite controversial (cf. 55,56), this clinical observation could point to a role for PRL in psoriasis. Weberet al believed that growth hormone (STH) is elevated in and causally related to the development of psoriasis, and proposed that the effect of bromocrip tine they had observed in psoriasis was due to its antagonism of STH (54, 57). The reportedly beneficial effect of somatostatin-infusionsin some patients with psoriasis (58, 59) was viewed as supportive of this theory, although somatostatin has multiple physiological actions besides the inhibition of STH release (59). Other authors, however, have not been able to detect significantly elevated serum STH or (closely STH-related)somatomedin C(IGF-1) levels in psoriasis (60,61,62), and diseases with elevated STH levels (e.g. acromegaly) ate not associated with a higher incidence of psoriasis (55). In addition, bromocriptine is not a classical STH inhibitor and can actually increase STH levels (11,55), whereas it is a very potent inhibitor of pituitary PRL release via its dopaminergic action on lacrotrophs(11). On this basis, any effect of bromocriptine on psoriasis is probably mediated by PKL, rather than by STH. Further clinical and experimental observations point into this direction. It is well appreciated that stress can trigger or exacerbate psoriasis (52, 63). While other authors have speculated that substance P accounts for this association of psoriasis and PFU (63), PRL is a likely alternative candidate - stress is among the stimuli increasing pituitary PRL release (1,ll). Whether pregnancy and lactation, states of transient hyperprolactinemia, also can trigger or exacerbate psoriasis, awaits further clarification. Although other peptide and steroid hormones are profoundly altered during their course, hidden indications to a PRL-skin connection in these ‘experiments of nature’ should not be overlooked. Impetigo herpetiformis (thought to be a rare form of pustular psoriasis), e.g., is exclusively associated with pregnancy (36). In a recent questionnaire study on the course of psoriasis during and immediately after pregnancy, it appeared that the disease remained mostly unchanged or even improved during pregnancy, while more than 50% of the patients experienced worsening of their psoriasis in the 3 months post partum (64) - an observation that could reflect the peak physiological PRL serum levels during lactation. Another clue can be construed from the Koebner phenomenon in psoriasis, which describes the development of psoriatic lesions in previously uninvolved

ROLE OF PROLAm

37

IN SKIN BIOLOCiY AND PATHOLOGY

skin by skin traumatization(52). A central controlling factor, which varies over time, appears to influence the response to injury in psorhuics, because the response to ‘Koebnerization’in a patient is the same at all skin sites at any given time. About 25% of psoriatits are ‘Koebnerpositive’, and individual patients can vary with time in their response to skin traumatization (52). Since Koebner positive patients have a higher T helper/suppressor ratio in uninvolved skin compared to Koebner negative patients, and since the resolution of psoriatic lesions is associated with an increase of activated T suppressor cells (52, 65), the reduced T suppressor cell function in patients with hyperprolactinemia (23) is immediately brought to mind: is PRL the humoral or local factor responsible for the state of the T helper/suppressor ratio with relevance to the Koebner response in psoriatic skin? Koe.bner negativity/positivity of psoriatics at different times might be modulated by PRL’s effect on the skin immune system. The results of bromocriptine therapy in psoriasis (54). in turn, may reflect a restoration of the intmepidermal T helper/suppressor ratio via the PRL-antagonistic action of this drug, especially since bromocriptine therapy restored the decreesed T suppressor cell function in some hyperprolactinemic patients (23). The immunological concepts of psoriasis postulate that psoriasis is a disorder of keratinocyte proliferation mediated by T lymphocytes, with emphasis on the role of activated intraepidermal T helper cells and an increased T helper/suppressor ratio (51, 52, 66). Which of the psoriasis-associatedimmunopathological phenomena (cf. 31, 32, 51, 52) could be explained by the immunomodulatory properties of PRL? Clearly, it is unlikely that a simple increase in PRL serum levels alone could initiate epidermal hyperplasia - there are no clinical reports of a higher incidence of psoriasis in patients with hyperprolactinemia (serum PRL levels and skin PRL receptors in psoriatics, however, have not been studied systematically so far). Therefore, the specific responsiveness of PRL target-cells in the skin to stimulation by this versatile hormone must be a crucial element in PRL-skin relations (e.g. over-expression of PRL receptors by keratinocytes, intraepidermal lymphocytes, dermal fibroblasts). The genetic predisposition for the development of psoriasis (51.52) could reflect such an inherently increased responsiveness to PRL stimulation. Two basic pathways can be envisioned for a PRLinduced or amplified keratinocyte hyperproliferation in psoriasis, based on an increased release of PRL by central or peripheral sites of PRL production (e.g. lactotrophs, lymphocytes, dermal fibroblasts) and/or

abnormal target-cell responsiveness to PRL stimulation: 1.

2.

inhibition of innaepidermal T suppressor lymphocyte functions (cf. 23, 52, 65). thus potentiating proliferative stimuli by T helper cells interacting with Langerhans cells (cf. 31, 32, 52, 66); PRL-stimulated over-production of kemtinocyte mitogens e.g. by activated T helper cells (cf. 28, 29, 31, 32) and dermal fibroblasts (IGF-1 (31, 32)). particularly in view of the abnormal functions of psoriatic dermal fibroblasts (51), which can induce keratinocyte hyperprohferation in vitro (67).

The most effective therapeutic regimens in the management of psoriasis (PUVA, steroids, CsA) have in common that htey reduce the number of intraepidermal T cells, thus restoring the allegedly imbalanced T helper/suppressor ratio in the psoriatic epidermal lesion (51, 52). Particularly,the effectiveness of CsA in psoriasis management lends credence to the pathways suggested above, since CsA is thought to preferentially inhibit the cytokine production by activated T helper cells (51), to compete with PRL for a common binding site (17, 43, 44, 88) and to be enhanced in its immunosuppressive potential by lowering of the prolactin serum level (45). In addition, CsA inhibits the PRL-mediated induction of omithine decarboxylaseand thereby the production of polyamines (43, 51.68). both of which are increased in lesional and non-lesional psoriatic skin (51). If CsA’s effect on keratinocyte proliferation is indeed related to its PRL-antagonism, then the steadily growing number of inflammatory skin diseases now reported to respond favorably to CsA treatment (including e.g. atopic and contact dermatitis (69)), mandates careful evaluation of the role of PRL in skin pathology. While psoriasis could serve as a model for elucidating this role, those skin diseases for which some associated PRL-disorder has already been noted, including acne vulgaris (47, 50), hidradenitis suppurativa (70). acanthosis nigricans (71). and systemic lupus erythematosus (72). would also be sensible study objects for probing the pro posed relation between PRL and skin disease. Such studies are particularly well-advised considering the high incidence of clinically often unimpressive hyperprolactinemiaand the alarmingly high percentage of clinically unsuspected pituitary microadenomas found during randomly selected autopsies (reportedly 15-25%!, of which 40% are immunohisto chemically positive for PRL (73)). Although it is not

38 known how many of these microadenomas actually secrete PRL, there is a fair chance that PI&-secreting microadenomas contribute to skin diseases and their clinical course, especially in those patients exhibiting an abnormal skin responsiveness to PRL. It is now necessary to systematically assess, on the one hand, associated skin disorders in all patients with known hyperprolactinemia (including e.g. patients on medication with neuroleptic drugs, most of which lead to a significant increase in the PRL serum level (74)) and, on the other, serum PRL levels and skin PRL receptors in all patients that exhibit dermatoses with indications to a possible involvement of PRL. A ‘pro&tin-circuit’

mDIcAL. IlwumEsm

tant mediator of epithelial-mesenchymal interactions in the skin. Furthe~om, PRL is now appreciated as a hepatotrophic hormone (1.81). This could shed new light on the long recognized, though still obscure association of liver and skin disease (82): PRL-regulated release of somatomedins from the liver (IGF1, synlactin) may affect the skin via stimulation of somatomedin receptors in the skin. Interestingly, patients with acromegaly commonly display marked overall hyperplasia of the skin and sebaceous glands as well as hyperuichosis (4). It is believed that the excess of STH in this disease leads to increased pro duction of IGF-I in the liver, which then stimulates skin IGF-1 receptors (4). PRL could operate via a similar mechanism.

may link skin and CNS. PRL, produced by pituitary cells (l), lymphocytes (16, 17, 18) or locally in the skin by fibroblasts(cf. 15), could 3. Immunomoduiation of lymphocyte, Langerhans affect epithelial cell function and proliferation in the cell, macrophage and natural killer cell function in the skin (cf. 17-26), thereby affecting the skin imskin via several pathways (cf. Fig); mune system and its regulatory circuits for the control 1. Binding to PRL receptors in the skin (e.g. on ker- of keratinocyte proliferation, in particular the release atinocytes, resident T lymphocytes, and/or dermal fi- of keratinocyte mitogens (27-32). Although most of broblasts). While functional PRL receptors have al- the immunomodulatory properties of PRL.have been ready been documented e.g. in frog skin (75) and a elucidated in rodent systems, human peripheral blood variety of human epithelial tissues (such as the skin- lymphocytes do exhibit PRL binding sites in vitro derived mammary gland and the prostate gland (1, (83, 88). A recent study in mice suggests that PRL 8, 9, lo)), their presence in human skin remains to is requited for the production of macrophage-actibe studied. That human T lymphocytes do express vating factors such as IFN-gamma by antigen-stimufunctional PRL receptors (83, 88) and ‘traffic’ into lated T cells (25). Considering the crucial role emergand from the skin (27, 28. 29) theoretically allows ing for IFN-gamma in the skin immune system (e.g. for PRL receptor-mediated effects on the skin even induction of HLA-DR expression on keratinocytes) in the unlikely event that other cells residing in the and the control of keratinocyte proliferation (32), this skin should turn out to lack such receptors. If the raises the question, whether a PRL-mediated disorder exciting demonstration of positive immunoreactivity in IFN-gamma production could contribute to hyperfor PRL in isolated human eccrine sweat glands, lo- proliferative skin diseases. That PRL stimulates thycalized mainly in the clear cells of the secretory coil mulin production of mouse thymic epithelial cells in (lOO), indicated osmoregulatory functions for PRL vivo and of human thymic epithelial cells in vitro in these skin appendages, the presence of functional and that it enhances proliferation of the latter cells PRL receptors in the skin would, of course, be a pre- in vitro (99) is particularly noteworthy in our context: this finding raises the possibility that PRL, simrequisite. ilarly, stimulates the production of T cell differentia2. Stimulation of somatomedin C (IGF-I) produc- tion factors by the quite closely related (28, 30, 104) tion in the liver (where IGF-1 is stimulated by STH epidermal keratinocytes as well as their proliferation. and PRL (1, 76)) or other peripheral sites of IGF-1 This argument is further supported by the observation production, such as dermal fibroblasts (cf. 15, 80). that the PRL-antagonisticdrug CsA not only leads to Receptors for IGF-1, which is a strong mitogen for drastic, but reversible atrophy of rodent thymic epkeratinocytes in vitro (77), have recently been doc- ithelial cells in vivo (103), but also inhibits human umented in cultured human keratinocytes (78) and epidetmal keratinocyte proliferation in vitro (102). Infresh sheets of human epidermis (79). Since IGF-1 creasing evidence suggests a role for PRL as an imcan be produced by dermal fibroblasts (3 1, 32, 80). munomodulatorof adult lymphocyte function (17-23) while the fibroblast production of IGF-1 can be stim- as well as of T and B lymphocyte development (26). ulated by serveral hormones and growth factors (80). Since these potentially PRL-modulated immunocomPRL-modulated IGF-1 production may be an impor- petent cells traffic into and from the skin (27-30),

39

ROLE OF PROLACITN JN SKIN BIOLOGY AND PATHOLOGY

where they may be subjected to further differentiation or proliferation signals from epidermal keratinocytes (28, 30), the pathway suggested here deserves intensive experimental evaluation, the more so if the cytokine production by epidennal keratinocytes itself should turn out to be in part PRL-modulated. 4. Modulationof the eflects of other hormones,mediators, cytokinesandlor neuropeptideson the skin e.g. by altering their metabolism, the expression of their specific receptors, and the intracellular signal transduction from these receptors. Though this pathway is a merely theoretical possibility, it is mentioned here because it has recently been reported that peripheral androgen metabolism can be modulated by PRL (40, cf. 84)). Homeostatic regulatory systems require feedback signals from the target organ (here, skin) to the signal transmitter (here, CNS). Such feedback signals, arising from the skin and modifying central PRL release, can indeed be envisioned. The figure briefly outlines some of them. Dependent on the permeability of the blood-brain-barrier for the respective feedback molecule and on its half-life, a multiplicity of agents produced by cells residing in or travelling through the skin (cf. 29, 30, 85, 86) may interfere with the complex CNS control (1, 87) of pituitary PRL secretion. Since the pituitary gland is not shielded from the peripheral circulation by the blood-brain-barrier and most of the venous blood drainage from the skin bypasses the liver, even short-lived messengers that are rapidly inactivated during their lirst liver passage and do not pass the blood-brain-barrier could directly interfere with pituitary PRL production and secretion. The figure lists a selection of skin-related signal molecules that are candidates for the role of feedback messengers in the proposed ‘prolactincircuit’, including IL-l, histamine, VIP, vitamin D3, EGF, FGF, prostaglandins and substance P, which have all been implicated as potential modifiers of PRL production and secretion (1, 11, 87, 89-92) and are produced in the skin (29, 30, 85, 86, 101). Although little is known about their precise role in the regulation of human pituitary PRL release in vivo (cf. 1, 87). pituitary lactotrophs could directly respond to stimulation e.g. with IL-1 (89) and vitamin D3 (1,87,91), which are produced by epidermal keratinocytes and released into the circulation (30). Such a ‘prolactin-circuit’ would not only help to explain the establishment of internal homeostasis in the proposed regulatory loop between the skin and the CNS, but would also integrate this hypothesis into the mainstream of neuroimmunology. Neuroen-

docrine hormones can modify the immune response and act as endogenous regulators within the immune system, while cytokines can modulate virtually all components of the neurnenti system; in addition, the immune and endocrine systems share a set of hormones and their receptors for intra- and intersystem communication (93). The bidirectional communication now recognized to occur between the immune and neuroendocrine systems (93,94) is likely to include the skin. In the light of increasing interest in skin neumpeptides (30,63,85,86) as well as in hormones (4,530) and cytokines (27-32) present in or generated by the skin, this raises the important question of the neuroimmunological control and function of the skin and its immune system. Evidently, a signal molecule that can combine immunodulatory, neuro endocrine, and growth regulatory properties geared at skin-related epithelial tissues - as PRL does deserves special attention in addressing this question. Conclusion Taken together, these multiple indications pointing to a role for PRL in skin biology and pathology, though scattered and not easily synthesized into a straightforward working hypothesis, have encouraged the suggestion of a ‘prolactin-circuit’ between the skin and the CNS. Despite its speculative nature and the fact that it is mainly based on rather circumstantial evidence, this unifying concept has attractive features. It links, for example, environmental and psychic stimuli via their effect on pituitary PRL production to the development of skin lesions (s. Fig.). This PRL circuitry thus integrates a whole body of clinical experience on the relatedness of skin and CNS: the tboughtful, but ill-understood clinical observations by earlier generations of physicians on the intricate relationship between skin and ‘psyche’ (cf. 49, 107) may find some biological explanation in the context of the suggested ‘prolactincircuit’. Specifically, the still conhoversial concept of ‘psychosomatic’ skin diseases (cf. 49, 107) would greatly benefit from the demonstration of measurable and experimentally reproducible molecular links (PRL?) between the skin and its diseases on the one hand, and the CNS on the other. If verified, the proposed concept would open new therapeutical avenues: current strategies for the treatment of skin disease could be supplemented with drugs that affect the PRL serum level (e.g. using new dopaminergic agonists (95)) or PRL receptors (since the PRL receptor has recently been characterized and cloned in the rat (%). it is to be expected that pharmacological modification of the activity and expression

40

MEDICALHYKnHESEg

of human PFU receptors will soon become possible.) In this context, investigative dermatology could profit from the extensive research effort aimed at one of the most intriguing epidermal derivatives - the mammary gland, an organ that unfortunately has become a strangerto dermatological research. Since lactation is possibly the most widely studied process of epithelial differentiation (97). the elucidation of the molecular biology of PRL-modulated epithelial cell differentiation and growth has made considerable progress in this field (cf. 8,97) and the transferof those findings to the fields of skin biology and pathology should offer insight into the molecular mechanisms underlying PRL’s postulated effects on epidermis and hair follicle. That a multifunctional organ as exposed to potentially lethal environmental influences and as vital for the survival of vertebrates in a constantly changing external milieu as the skin must be tightly controlled by the CNS and must be capable of communicating with it on multiple levels, is almost a truism (particularly, if one considers the common embryologic origin of skin and CNS). Yet, while immunology and immunopathology of the skin have been a major focus of dermatological research during the past two decades, very little is known about the neuroendocrine and neuroimmunological control of the skin and the humoral feedback signals sent from the body’s largest organ to the CNS. Considering, furthermore, that the clinical implications of the neuroendocrineimmune connection (cf. 98) will become increasingly important for the effective management of skin diseases, particularly of common inflammatory skin diseases such as psoriasis, u&aria and atopic dermatitis (cf. 107). a ‘neuroimmune-dermatological’ approach is warranted. Thus, focussing on PI&, an immunomodulatory and growth-regulatory hormone uniquely suited to serve as a messenger between neuronal, mesenchymal and epithelial tissues, could boost the development of a new medical subspeciality - ‘neuroimmunodermatology’. Such a research focus may not only improve the treatment of skin and hair diseases, but it also promises to enhance our understanding of the fascinating molecular connections between skin, immune, endocrine, and nervous system in health and disease. Acknowledgement I am most grateful to Dr Steven Rob&k for numerous inspiring discussions on the topic, critical and untiring review of the manuscript, and for preparation of the figure.

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